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type-I mechanism. This is so far the only exception to the well-accepted
ÒÓðå-Ï mechanism of PDT.
Pandey and Zheng
Scheme 72. Dimers with amide linkages.
343 R = CH=CH2
344 R = CH(0-hexyl)CH3
0 = C-NH-CH2-CH2-CH2-CH2-CH-NH-C=0
345 R = CH=CH2 C02Et
346 R = CH(0-hexyl)CH3
0=CNH(CH2)3NH2 C02Me C02CH3 348
0=CNH(CH2)3NH-C=0 C02Me C02CH3
Localization and photodynamic efficiency of a mono-cationic porphyrin
(MCP) 453 from 452 were assessed by Kessel and coworkers.338 The
therapeutic response to MCP appeared to be related mainly to vascular
Certain cationic porphyrins containing glycosyl groups 454-461 were
also reported by Krausz and coworkers (Scheme 93).346 In these compounds
the presence of a sugar moiety increased the water solubility and
membrane interaction; however, no PDT data are reported.
In their attempts to improve the photodynamic action of cationic
porphyrin, Zimmermann and coworkers prepared a series of new cationic
phthalocyanines with lipophilic side chains 462-465 (Scheme 94).340 It
was found that these
cationic sensitizers specifically accumulate in the inner mitochondrial
membranes and that the cationic lipophilic ZnPcA6 463 has the strongest
Michelsen et al. reported a new class of cationic photosensitizers 466
for PDT.341 These unsymmetrical substituted benzonaphthoporphyrazines are
synthesized to have one to eight positive charges. The Q-band transition
exhibits a red shift from 680 to 760 nm dependent upon the number of
annealed naphthalene rings. The singlet-oxygen yields of these compounds
are normally higher compared with zinc phthalocyanine.
Another interesting approach reported by Driaf et al.342 involves the
synthesis of glycosylated cationic porphyrins
43/Porphyrins as Photosensitizers in Photodynamic Therapy
Scheme 73. Examples of expanded porphyrins.
= N HN'
353 Stretched Porphycene
356 Vinylogous Porphyrin
X = CH2 or N 351 Homoporphyrin
467-471. The rationale was that O-glycosylation of the cationic
porphyrins may increase cell-membrane interactions, and the various
lipophilic substituents will allow for increased penetrability of
porphyrins across the cell membrane.
XIII. Phthalocyanines and Naphthalocyanines
Observations that neoplastic tissues have affinity for phthalocyanines
(Pc) 472 were first reported by Wrenn et al.347 and later by Frigerio et
al.34S However, interest in Pc as photosensitizers for PDT started in
1985 following the
report by Ben-Hur et al.349 to show their ability as photosensitizers in
Phthalocyanines (Pc) 472 and naphthalocyanines (Nc) 473 can be
regarded as azaporphyrins containing a ring system containing four
isoindoles linked by nitrogen atoms (Scheme 95).350 Compared to
Photofrin, Pc and Nc offer high molar-extinction coefficients (e = ~ 105)
and red-shift absorption maximums at 680 nm Pc and 780 nm Nc resulting
from the benzene or naphthalene rings condensed to the periphery of the
porphyrin-like macrocycle.351 Pc and Nc are excellent singlet oxygen (Þ2)
generators. Interestingly, chelation of a metal ion such as zinc or
aluminum increases the singlet-oxygen efficiency to nearly 100%.352
Pandey and Zheng
Scheme 74. Texaphyrins.
R air/ base
364 R1 = R2 = H
365 R1 = H, R2 = Me
366 R1 = H, R2 = OMe
367 R1 = H, R2 = -0(CH3CH20)4-
368 R1 = H, R2 = 0(CH2)30H
369 R1 = CH2OH, R2 = 0(CH2)30H
370 R1 = CH2OH, R2 = H
R1 = = H
372 [M](n'1)+ R1 = H, R2 = Me
373 [M](n'1)+ R1 = H, R2 = OMe
374 [M](n'1)+ R1 = H, R2 = -0(CH3CH20)4-
375 [M](n'1)+ R1 = H, R2 = 0(CH2)30H
376 [M](n'1)+ R1 = CH2OH, R2 = 0(CH2)30H
377 [M](n'1)+ R1 = CH2OH, R2 = H
M = Cd(ll), Zn(ll), Hg(ll), Mn(ll), etc.; n=2
Thus, metal complexes of Pc and Nc are of particular interest for PDT.
Besides being able to insert different metal ions into the ring, the Pc
and Nc macrocycle can be derivatized by other methods. For instance,
various groups can be added to the outer rings of the isoindole units; if
the valency of the central metal ion is higher than 2, it binds various
axial ligands. All of these chemical changes of the Pc and Nc skeleton
can alter their PDT efficacy. Meanwhile, addition of bulky axial-ligand
substituents to these molecules should reduce their tendency to
aggregate, favoring the monomeric and photoactive form of the sensitizer.
The aggregated Pc and Nc are inactive photochemically because of greatly
enhanced rate of excited singlet state deactivation by internal
conversion to the ground state.